Although, the lifespan with SLE has improved considerably over the last several decades, safer and more effective therapies as needed. The discovery of costimulatory molecules has led to the consideration of new therapies for SLE aimed at decreasing activation thresholds of both B and T cells. Use of costimulatory blocking agents in appropriate combinations may allow us to treat SLE flares with short term regimens, so as to avoid the morbidity associated with long term immunosuppressive therapy. In Aim 1 of this proposal we will develop modulators of two newly discovered members of the B7/CD28 and TNF/TNFR families and test them in prevention and remission induction studies in SLE prone mice in combination with a knock effective agent, CTLA4Ig. The CD28 like molecule ICOS that costimulates activated T cells and secondary B cell responses will be blocked with a soluble murine ICOS-IgG2a fusion. The CD40L like molecule BAFF, that costimulates both naive B cell development and germinal center formation, will be blocked with either a dimeric or pentameric fusion protein of its receptor TACI. In Aim 2 we propose to understand at which stage of C cell development these new agents are effective by using novel methods of isolating populations of naive and antigen activated autoreactive B cells that can be studied using a variety of immunochemical and molecular techniques. In Aim 3 we will determine the effect of CTLA4Ig with and without addition of ICOS or BAFF blockade on two populations of T cells that may influence disease progression- memory and NK T cells. The mechanistic studies proposed in this application will have direct clinical relevance because they permit us to understand the effect of showing signs of disease activity. As immune modulating agents begin to enter early clinical trials in humans, understanding their short and long term effects on the B cell repertoire and B cell activation in the autoimmune host is critically important. Analysis of the pathways that are inactivated by these new reagents will pave the way towards development of more specific targeted therapy for SLE.